Targeting Oncogenic RAS in Pediatric Leukemia
Background: One of the most deadly but un-drugged cancer-causing proteins is called RAS. RAS mutations are present in approximately 20% of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), 25% of juvenile myelomonocytic leukemia (JMML), and up to 50% of pediatric mixed lineage leukemia (MLL-ALL). Pediatric leukemias bearing RAS mutations are typically associated with resistance to cancer treatment and reduced overall survival. Therefore, new insights into the mechanisms of RAS regulation are urgently needed in order to guide drug development strategies. We have developed “stapled peptides” modeled after a protein domain that interacts with RAS proteins and discovered that our compounds can directly inhibit RAS by a new mechanism. In addition to dissociating a helper protein, called SOS1, from RAS, we surprisingly found that our stapled peptides can block RAS directly.
Project Goal: The purpose of this research is to apply chemical, structural and biological approaches to characterize this new mechanism of RAS blockade and, in doing so, advance a new therapeutic strategy for pediatric leukemia that overcomes RAS-driven treatment resistance.
Project Update 2021: We have applied structural methods to investigate both the conformational consequences of oncogenic Ras mutations and the influence of KRAS inhibitors, ranging from stapled peptides to small molecules, on structure and function. The distinctive mechanisms of action informed new opportunities for combinatorial treatments that could be synergistic in combating Ras-dependent pediatric leukemias. Lead stapled peptides demonstrated striking serum stability compared to the unstructured template sequence, setting the stage for in vivo efficacy testing once iterative optimization yields analogs within the goal potency range. The critical importance of oncogenic Ras proteins as pathologic drivers of diverse pediatric leukemias mandates persistence in the longstanding quest to disarm this vicious cause of relapsed and refractory disease.
